The present invention relates to local biotherapeutic delivery in cardiac regions, and more particularly to devices and processes for locally delivering therapeutic agents such as controlled release proteins, cell based therapies, and gene based therapies for treating heart failure, stenosis, ischemia, arrhythmias, hypertrophic cardiomyopathies, infarction, and vulnerable plaque. The invention also relates to therapeutic strategies incorporating percutaneous intramyocardial delivery catheter systems for transendocardial delivery from within the ventricles of the heart, selected biopharmaceutical agents, sustained delivery means, and geometrical and temporal delivery protocols, targeted towards indications within cardiovascular disease, including coronary artery disease (including stenosis, restenosis, vulnerable plaque, and ischemia), congestive heart failure, myocardial infarction, atrial cardiac conduction disorders, and ventricular cardiac conduction disorders.
Coronary Artery Disease (CAD)
Blood flow to the heart muscle can be severely reduced by atherosclerotic disease of the coronary arteries, which accounts for most ischemic heart disease. Insufficient oxygen to the heart muscle as a result of restricted blood flow can lead to myocardial ischemia, and possibly to a heart attack or death. Restoring blood flow is the most effective method to relieve painful ischemic symptoms and to reduce the long-term risk of a heart attack.
Current treatments for coronary artery disease include drug therapy, coronary artery bypass surgery and catheter-based treatments, including angioplasty, atherectomy and coronary stenting.
Restenosis
Today, local drug therapies are delivered from the surfaces of stents to reduce the potential for restenosis after percutaneous transluminal angioplasty, with or without stent placement.
Vulnerable Plaque
In recent years the cause of a myocardial infarction has been identified as thin walled plaques in relatively open vessels. Vulnerable plaques are predisposed to suddenly come free from the artery wall, and may occlude a vessel. Vulnerable plaques often are characterized as having a lipid core and being “hot” in that they are slightly warmer than surrounding tissue. The ability to identify and treat vulnerable plaques before they cause myocardial infarction is in active development.
Cardiac Ischemia
Cardiac ischemia occurs when a coronary artery is partially or completely obstructed, such as due to atherosclerosis. A sudden, severe blockage of a coronary artery may kill part of the heart muscle (heart attack). Cardiac ischemia may also cause an abnormal heart rhythm (arrhythmia), which can lead to fainting or even sudden death. Treatment is directed at improving blood flow to the heart muscle, and may include medication, exercise, angioplasty, and bypass surgery.
Heart Attack/Myocardial Infarction (MI)
A heart attack occurs when a blockage in a coronary artery severely restricts or stops blood flow to a portion of the heart. When blood supply is greatly reduced or stopped for a sufficient time, heart muscle cells die. Heart muscle cells generally lack the ability to multiply to replace the dead cells. After a heart attack, white blood cells migrate into the area and remove the dead heart muscle cells, and fibroblast cells proliferate and form a fibrous collagen scar in the affected region of the heart. Following a heart attack, the heart's ability to maintain normal function will depend on the location of the damage and the amount of damaged tissue.
Current therapeutic treatments for heart attack include drug therapy to dissolve a blood clot immediately following a heart attack, medicines to alleviate symptoms, and certain lifestyle changes, such as an altered diet, increased exercise levels and cessation of smoking.
Congestive Heart Failure (CHF)
Congestive heart failure is caused when the heart is unable to contract adequately to pump blood throughout the body. The normal physiological stimulation of heart function is generated when chemical transmitters known as catecholamines bind with certain receptors on the surfaces of heart cells, triggering a series of events that result in increased heart rate and increased force of contraction. Typically, in congestive heart failure, the heart is unable to respond adequately to catecholamines.
Current treatments for congestive heart failure include drug therapy, and rarely, heart transplantation. Drug treatments generally treat symptoms only, and have a limited effect on the progression of the disease.
Cardiac Conduction System Disorders
The rhythmic contraction of the heart essential for its function as a pump is enabled by the conduction of electrical signals between cells and along specialized conducting networks within the heart such as the sinoatrial node, the atrioventricular node, and the perkinje fibers. To date, disruptions in these conduction pathways have been treated either by tissue ablation to remove a pathway, or by the implantation of devices designed to pace the heart (pacemakers) or to jump start the heart after disorganization of the electrical signals (defibrillators).
One conduction system disorder, atrial fibrillation (AF), may be treated with an atrial defibrillator to deliver energy to the atrium to terminate arrhythmias. However, this therapy is painful, has the potential to initiate life threatening ventricular arrhythmias, and requires an expensive cosmetically undesirable permanent implant.
Doctors have treated atrial fibrillation with drugs administered intravenously or orally. U.S. Pat. No. 5,527,344 (Arzbaecher) describes a pharmacological atrial defibrillator and method for automatically delivering a defibrillating drug into the blood stream upon detection of atrial arrhythmias. The defibrillating drug is injected in a large initial dose followed by a continuous smaller dose. If the injected drug is to have an effective concentration within the heart, a large amount must be injected into the blood stream, risking undesirable side effects in other organs.
Atrial fibrillation also is treated by atrial ablation by heating tissue with RF energy, laser energy, ultrasound energy, by cooling tissue, by surgically cutting the tissue, or by infusing tissue with an ablative medium such as ethanol or phenol.
Arrhythmias similar to atrial fibrillation also are treated with ablation. For example, conduction over the fast and slow pathways of the AV node can occur simultaneously, leading to a double ventricular response from each atrial beat that may present as symptomatic, incessant, and irregular narrow-complex tachycardia which may be misdiagnosed as atrial fibrillation. Slow AV nodal pathway focal ablation can stop tachycardias and restore ventricular function when cardiomyopathy is present. Other arrhythmias may be treated with similar ablative approaches.
There are two general approaches for providing ablative therapy to the heart to treat atrial fibrillation: the long linear ablative lesion approach, and the focal ablation approach. In the long linear ablative lesion approach, heart tissue is killed along a linear pathway, to segment the heart into regions too small to sustain atrial fibrillation. In the focal ablation approach, the heart tissue is killed at a single site, to ablate the region of the heart that prematurely depolarizes and acts as a trigger to initiate atrial fibrillation. Focal ablations remove triggers that initiate atrial fibrillation, often within the pulmonary veins or in the region near the junction of the veins with the left atrial tissue.
Many of these treatments require sensing electrical activity in cardiac tissue to determine whether a particular location is appropriate for a selected treatment, or to measure electrical activity after ablation therapy to determine whether the intended result has been achieved. Frequently there is a need to image tissue surrounding a selected treatment site.
In conjunction with supplying treatment agents locally to a designated site, there is a need for the option to supply several different agents to a given site while ensuring that the agents do not mingle until reaching, or nearly reaching, the treatment site. Finally, in conjunction with using a contrast fluid to fluoroscopically image a treatment site, there is a need for applying an agent to the treatment site in relative isolation from the contrast fluid.